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Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of 98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. Conclusion: The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease.

OBJECTIVE: Hepatitis C virus (HCV) infection has been associated with the production of autoantibodies and the development of several autoimmune disorders. Immune thrombocytopenic purpura (ITP) is an immune-mediated syndrome of unknown etiology characterized by the presence of autoantibodies against platelet membrane proteins. METHODS: Retrospective chart review. RESULTS: Seven patients with chronic HCV infection (five with cirrhosis and two with chronic active hepatitis) developed thrombocytopenia, out of proportion to their liver disease, and were diagnosed with ITP based on the presence of anti-platelet antibodies and their response to treatment. The number of patients with ITP which occurred in a population of 3440 HCV patients seen over this time interval is much greater than would be expected by chance (p < 0.00001). Six patients required treatment and four required hospitalization. Four of the six responded to corticosteroids alone. Both of the patients who failed to respond to corticosteroids responded to cyclophosphamide. No mortality occurred from complications of thrombocytopenia. CONCLUSIONS: ITP occurs more commonly in patients with chronic HCV infection than would be expected by chance. This should be considered in patients with liver disease and unexplained thrombocytopenia, as well as in patients with newly diagnosed ITP. Evaluation of antiplatelet antibodies, using an antigen-specific assay, was useful in supporting this diagnosis. Therapy with either corticosteroids or cyclophosphamide was successful in the six patients who required treatment.

BACKGROUND & AIMS: Eradication of Helicobacter pylori expedites duodenal ulcer healing and prevents recurrences. Most patients with duodenal ulcers have impaired proximal duodenal mucosal bicarbonate secretion (DMBS). In patients with inactive, healed duodenal ulcers and normal subjects, the effect of H. pylori infection on DMBS and proximal duodenal secretory function and structure were examined. METHODS: DMBS was quantitated before and after eradication of H. pylori. Mucosal structure (duodenal bulb histopathology) and function (DMBS at rest and stimulated, effect of active vs. healed ulcer and of age) were determined in patients with duodenal ulcers and normal subjects. RESULTS: In patients with duodenal ulcers, H. pylori eradication normalized proximal DMBS. Histological examination of duodenal biopsy samples was comparable in patients with duodenal ulcers and normal subjects without apparent relationship between inflammation and DMBS. Significantly impaired DMBS occurred in response to all agonists tested (luminal acid, prostaglandin E2, and cephalic-vagal stimulation) in patients with duodenal ulcers, suggesting a generalized secretory defect. Neither the presence of active (vs.inactive) ulcer nor age significantly affected bicarbonate secretion. CONCLUSIONS: In patients with duodenal ulcers, eradication of H. pylori normalized proximal DMBS and may thereby reduce ulcer recurrences. Altered DMBS in patients with duodenal ulcers was unrelated to histopathologic abnormalities. Impaired bicarbonate secretion in patients with duodenal ulcers could be caused by a cellular and/or physiological regulatory transport defect possibly related to H. pylori. (Gastroenterology 1996 Mar;110(3):705-16)

Influenza virus infection may cause significant complications in liver transplant recipients, and whether vaccination is effective in these patients is controversial. We performed a study to assess the immune response to influenza vaccine in liver transplant recipients and patients with cirrhosis compared with healthy controls. Liver transplant recipients (n = 20), patients with compensated cirrhosis awaiting transplantation (n = 14), and healthy volunteers (n = 9) were administered the standard dose of the 1999 to 2000 inactivated trivalent vaccine (A/Bejing/262/95[H1N1]; A/Sidney/5/97[H3N2]; B/Yamanashi/166/98). Antibody responses to each component of the vaccine were measured at baseline and after 6 weeks by hemagglutination inhibition. Vaccination was well tolerated, and no major side effects were observed. A significant postvaccination increase in antibody titer to all 3 vaccine components was obtained in all groups. However, liver transplant recipients had significantly lower postvaccination geometric mean titers and geometric mean increases to the H3N2 component compared with patients with cirrhosis and controls. The rate of seroconversion to H3N2 after vaccination was also significantly lower in liver transplant recipients (15% v. 89%). We conclude that liver transplant recipients have a significantly impaired immune response to the influenza vaccine, and some patients may remain unprotected from influenza infection after vaccination. Further studies of modified protocols of influenza vaccination for these patients are recommended.

Radiographic study following inversion ankle sprain commonly is used to determine the presence of anatomic laxity across the talocrural joint.To compare the degree of talar tilt derived from a radiographic ankle stress exam under 2 conditions: self-stress vs manual stress applied by the clinician.Twenty-four subjects seeking medical care following ankle sprain underwent talar tilt stress exams of both ankles. The involved ankle was imaged with self-stress by use of a strap and with the clinician providing manual stress during the imaging exam. Mean talar tilt for the self-stress method was 2.2 degrees, compared with 5.9 degrees for the manual stress method (P.001).Significantly greater and clinically meaningful differences in talar tilt angle were found when manual stress was provided by the clinician. To avoid false negative findings of anatomic laxity in stress talar tilt studies at the ankle, a standardized procedure in which the clinician provides manual stress may be necessary.

Background Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. Methods At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 μg per kilogram of body weight per week or a low dose of 1.0 μg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 μg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa2b regimen and the peginterferon alfa-2a regimen. Results Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P = 0.20 for standarddose vs. low-dose peginterferon alfa-2b; P = 0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], −2.3 to 6.0) between standard-dose and low-dose peg interferon alfa-2b and −1.1% (95% CI, −5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for lowdose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. Conclusions In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon– ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials. gov number, NCT00081770.)

Background/Aims ISIS 14803 is a 20-unit antisense phosphorothioate oligodeoxynucleotide that binds to hepatitis C virus (HCV) RNA at the translation initiation region of the internal ribosome entry site (IRES) and inhibits protein expression in cell culture and mouse models. This Phase I, open-label, dose-escalation trial of ISIS 14803 was performed in chronic HCV patients. Methods At least 7 days after receiving an initial single dose, twenty-eight patients received 0.5–3mg/kg ISIS 14803 thrice weekly for 4 weeks by intravenous infusion or subcutaneous injection. Results In most patients, the 4-week treatment did not reduce plasma HCV RNA. However, 3 patients receiving ≥2mg/kg had transient HCV reductions of 1.2–1.7log 10 that persisted ≤32 days. These reductions were accompanied by asymptomatic, self-resolving elevations in serum alanine transaminase (ALT) levels to >10× the upper limit of normal. Two other patients had ALT flares without plasma HCV reduction. No clinical signs, symptoms of hepatic dysfunction, or laboratory changes in albumin or prothrombin time accompanied ALT elevations. Conclusions ISIS 14803 treatment was associated with HCV reductions in only 3/28 patients. ALT flares in 5 patients also occurred. Further studies to evaluate ISIS 14803 treatment and the mechanisms of the ALT flares are now required.

Background: The efficacy of sofosbuvir (SOF)-containing regimens in patients who failed to achieve sustained virologic response (SVR) with SOF remains unknown. Given the lack of genotypic or phenotypic resistance to SOF in patients who did not achieve an SVR in the Phase 3 program, we designed an open-label study for relapsers to receive either a longer duration of SOF + RBV (24 weeks) or SOF + RBV with peginterferon (PEG-IFN). Methods: GT-2 and GT-3 HCV infected patients who failed either 12or 16-week regimens of SOF + RBV (Phase 3 studies: FISSION, FUSION, and POSITRON) were offered either 12-weeks of SOF (400 mg once daily) + PEG-IFN (180μg weekly) + RBV (1000-1200 mg daily) or an interferon-free 24-week arm of SOF+RBV. The choice of regimen was based upon investigator discretion. The primary efficacy endpoint is SVR12 and the secondary efficacy endpoint is SVR4. Results: A total of 97 GT-3 and 16 GT-2 patients have been enrolled. The majority of patients were male (80%) with a non-IL28CC genotype (65%) and 33% of patients had cirrhosis. To date, overall SVR4 rates are 96% (27/28) for GT-3 and 100% (6/ 6) for GT-2 infected patients. The table displays these data for patients who have reached the 4-week post-treatment visit. Conclusions: Retreatment with sofosbuvir regimens of longer duration or with the addition of PEG-IFN in prior SOF failures results in high SVR4 rates and appears to offer a viable approach for GT-2 or GT-3 HCV infected patients who fail to achieve an SVR with SOF+RBV regimens.

Ribavirin, a nucleoside analogue, inhibits replication of RNA and DNA viruses and may control hepatitis C virus (HCV) infection through modulation of anti-inflammatory and antiviral actions. Ribavirin monotherapy has no effect on serum HCV RNA levels. In combination with interferon, this agent appears to enhance the efficacy of interferon. The aim of this study was to monitor serum HCV RNA levels early during therapy with interferon and ribavirin compared with that previously seen in the same patients during interferon monotherapy. Five patients who previously showed no response to therapy with interferon alfa 3 MU three times weekly for 6 months were retreated with the identical dose of interferon alfa 2b in combination with oral ribavirin 1,000 mg/day. Serum HCV RNA levels were monitored at baseline, week 4, week 8, and week 12 of therapy by a quantitative multicycle polymerase chain reaction assay. In the first 8 to 12 weeks, serum HCV RNA levels showed a greater decrease in all patients when retreated with combination therapy compared with interferon alone. Mean (+/- SEM) serum HCV RNA levels for interferon therapy alone were 3.3 +/- 0.95, 1.2 +/- 0.95, 1.6 +/- 1.2, and 2.3 +/- 1.2 x 10(6) copies/ml at week 0, 4, 8, and 12, respectively. This was compared with 3.3 +/- 0.83, 0.3 +/- 0.2, 0.03 +/- 0.02, and 0.15 +/- 0.14 x 10(6), respectively, for the interferon and ribavirin group (p < 0.07 at week 8). Two of five patients had undetectable serum HCV RNA during combination therapy. Combination therapy with interferon and ribavirin in prior interferon nonresponders reduces serum HCV RNA levels compared with interferon alone. This may suggest some additional antiviral effect of ribavirin when given with interferon.